Given USP15s role in tumorigenesis and T cell activation, USP15 is a promising target for cancer and cancer immunotherapy. Identification of USP15-specific small-molecule inhibitors through a quantitative high-throughput screening and further development of the lead compound could not only open new strategies to tackle cancer, but allow to better understand biological functions of USP15. During this period, the project team worked to validate small molecule hits from the previously completed high-throughput screen. Using activity profiles from the orthogonal assays tested against the screening hits, the team employed a machine learning approach to conduct an in silico screen against an additional 100,000 small molecules to extend the number of prospective chemotypes with inhibitory activity against USP15.